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Our Approach

A Next-Generation PDE4 Prodrug

Rationally designed to improve the therapeutic profile of a validated target in immune-mediated and fibrotic diseases.

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Why Our Approach Is Different

HISTORICAL ORAL PDE4 INHIBITORS

Validated biology with important limitations

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VALIDATED TARGET

PDE4 is a clinically validated target that regulates cAMP and plays a central role in immune response, inflammation and fibrosis.

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HISTORICAL LIMITATIONS

  • GI / CNS side effects
  • Short half-life
  • Twice-daily dosing
  • Systemic exposure limitations

PALI-2108

A differentiated prodrug design
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PALI-2108 SOLUTION

  • Targeted bioactivation in the terminal ileum and colon
  • High intestinal tissue exposure
  • Sustained PDE4 inhibition above IC90 with once-daily dosing
  • Once-daily oral dosing
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POTENTIAL BENEFITS

  • Improved tolerability potential
  • Once-daily convenience
  • Combination potential
  • Broad applicability across inflammatory and fibrotic diseases

PDE4 in Immune Regulation, Inflammation and Fibrosis

Immune Regulation

PDE4 regulates cAMP signaling, a key modulator of immune-cell activation and inflammatory responses.

Inflammation

Elevated PDE4 activity promotes inflammatory mediators, including TNF-α, IL-6 and IL-17.

Fibrosis & Tissue Remodeling

PDE4 signaling contributes to fibroblast activation, extracellular matrix production and tissue remodeling.

PALI-2108 Differentiated Prodrug Design

Oral
Administration

PALI-2108 is administered orally as an inactive prodrug.

Targeted
Bioactivation

The prodrug is activated by bacterial enzymes in the terminal ileum and colon.

High Intestinal
Tissue Exposure

The active PDE4 inhibitor achieves high concentrations at sites of disease.

Sustained Systemic
PDE4 Inhibition

Sustained plasma exposure supports continuous PDE4 inhibition and once-daily dosing.

Phase 1 Human Pharmacology

High Intestinal Tissue Exposure with Sustained Systemic PDE4 Inhibition Above IC90

Key takeaways from Phase 1 human pharmacology

High Intestinal Exposure

Achieved high intestinal concentrations with once-daily dosing.

Sustained PDE4 Inhibition

Plasma concentrations maintained above IC90 through 24 hours.

Well Tolerated

No serious adverse events reported.

PHASE 1 DATA IN HEALTHY VOLUNTEERS (n=12) (15, 30 AND 45 MG ONCE-DAILY DOSING)

Day 1 versus Day 9 plasma pharmacokinetics

15 mg30 mg45 mgIC50 0.64 ng/mLIC90 9.1 ng/mL
Day 1First Dose
0.2 0.5 1 2 5 10 20 50 100 0 4 8 12 16 20 24 Hours Plasma concentration (ng/mL)
Day 9Repeat Dosing
0.2 0.5 1 2 5 10 20 50 100 0 4 8 12 16 20 24 IC90 9.1 ng/mL IC50 0.64 ng/mL Hours

Concentration axis is logarithmic. Data shown are mean values from the Phase 1 healthy volunteer study.

PHASE 1b DATA IN FIBROSTENOTIC CROHN’S DISEASE (n=5)
(POOLED ACROSS 20, 25, AND 30 MG ONCE-DAILY DOSE COHORTS)

High Intestinal Tissue Exposure Across the Ileum and Colon

Tissue pharmacokinetic profile by GI segment (pooled across dose cohorts)

050100150200250300350400 IC90 (PDE4) 9.1 ng/mL Tissue concentration (ng/mL) Mean 107.6 ng/mL Ileum Mean 185.4 ng/mL Ascending Colon Mean 114.4 ng/mL Descending Colon

Mean with standard deviation shown as error bars.
Tissue samples collected at steady state approximately 4–8 hours post-dose prior to ileocolonoscopy.
Linear scale.

ILEUM

107.6

ng/mL

ASCENDING COLON

185.4

ng/mL

DESCENDING COLON

114.4

ng/mL

MEAN ACROSS GI SEGMENTS

149.0

ng/mL

PEAK PLASMA Cmax (ALL DOSES)

19.4

ng/mL

MEAN TISSUE / PLASMA RATIO

~7.3×

Higher mean intestinal tissue concentrations relative to peak plasma concentration

IC90 (PDE4) = 9.1 ng/mL
IC50 (PDE4) = 0.64 ng/mL
Cmax = Peak plasma concentration

Validated Biology. Precision Prodrug Design. Differentiated Pharmacology.

Palisade Bio is advancing PALI-2108 to realize the potential of PDE4 inhibition in inflammatory bowel disease.